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Leader of the Psoriasis Study Centre
Department of Dermatology and Allergy
University Hospital Charité
Psoriasis is a chronic skin disease that affects 1–3% of the population worldwide. Scaling and inflammation of the skin are typical hallmarks of the disease. Up to 20% of patients also show affliction of joints and nails.(1–3) Physicians estimate that psoriasis affects about five million people in Europe.(4) Many patients can be treated with topical ointments or UV therapy, but in more severe cases (about 20% of all psoriasis patients) systemic therapy is required. Available systemic treatments are limited due to insufficient clinical responses, especially a lack of long-term efficacy, or due to contraindications or side-effects (eg, nephrotoxicity of ciclosporin or hepatotoxicity of methotrexate).(2,3) Today, psoriasis is believed to be a T-cell-mediated (auto)immune disease(1,5,6) in which lymphocyte activation plays a crucial role.(7) The growing knowledge of the immunopathogenesis of psoriasis and the use of new biotechnology and genetic engineering techniques made it possible to create new biological agents – molecules that either mimic the actions of normal human proteins or interact with circulating proteins or cellular receptors. These agents are mainly monoclonal antibodies, fusion proteins, toxin-coupled proteins or recombinant proteins. Therapeutic strategies target the inhibition of T-cell activation, the depletion of activated T-lymphocytes, the inhibition of adhesion of inflammatory cells, the inhibition of the effects of proinflammatory cytokines and the application of anti-inflammatory cytokines.(8–10) Several review articles about biological agents in psoriasis therapy have been published recently.(8–15) This article reviews clinical treatment with four biologicals that are now coming into use – alefacept, efalizumab, infliximab and etanercept – and briefly discusses their use in clinical practice.
Alefacept is a recombinant fusion protein, composed of the terminal portion of leukocyte function molecule-3 (LFA-3, or CD58) and the Fc part of human immunoglobulin (Ig) G1. It blocks the interaction between LFA-3 on antigen-presenting cells and its ligand CD2 on memory effector T-cells by competitive binding and, thus, inhibits their activation and proliferation. A second immunosuppressive effect is the ability of alefacept to form a bridge between CD2 on CD45RO+ T-cells and the FcgammaIII receptor (CD16) on natural killer (NK) cells. This induces apoptosis of T-lymphocytes through the release of granzyme by NK cells.(16)
Experience and application
Alefacept is manufactured by Biogen and is available as intramuscular (15mg) or intravenous (7mg) injections. It is given once weekly. In a phase III placebo-controlled trial with 533 patients, alefacept proved to be effective in about one-third of patients (28% of patients reached psoriasis area and severity index [PASI]-75 after 12 weeks of treatment, 40% after a second treatment course) and maintained a 50% or greater reduction for a median duration of more than seven months. Alefacept is well tolerated. The most common side-effects are chills, headache, rhinitis, pharyngitis and pruritus. Alefacept reduces the number of CD45RO+ T-cells and, therefore, T-cells need to be monitored during treatment.(16–20)
The FDA approved alefacept in January 2003. Candidates for alefacept are patients with moderate-to-severe psoriasis who need systemic treatment. Approval is still pending in Europe.
Efalizumab is a recombinant humanised IgG1 kappa monoclonal antibody that binds to human CD11a, the a-subunit of leukocyte function antigen-1 (LFA-1), which is expressed on all leukocytes. It inhibits the binding of LFA-1 to ICAM-1 (CD54), and also ICAM-2 and ICAM-3, and thus influences the activation of T-lymphocytes, their adhesion on endothelial cells and their migration to sites of inflammation.(21)
Experience and application
Efalizumab is produced by Serono and Genentech. It is given by subcutaneous (SC) injection once a week, starting with an initial dose of 0.7mg/kg of body weight and maintained at 1.0mg/kg. Results of a phase III trial showed that nearly 30% of patients after 12 weeks and 43% of patients after 24 weeks of therapy achieved a 75% or greater improvement in their PASI score. Efalizumab was well tolerated. Patients experienced mild-to-moderate flu-like symptoms, headache and chills, especially after the first few doses.(21–24)
Efalizumab received EU approval for the treatment of patients with moderate-to-severe plaque psoriasis failing to respond to or having contraindication to other systemic therapies in October 2004. It has been available in the USA since November 2003.
Tissue necrosis factor alpha (TNFalpha), an inflammatory cytokine, induces the synthesis of numerous proinflammatory cytokines via activation of nuclear factor kB (NFkB),(25) and contributes, among others, to the accumulation of inflammatory cells in the skin by increasing the expression of ICAM-1 on endothelial cells and keratinocytes. Two strategies are possible for neutralisation of TNFalpha: with monoclonal anti-TNFalpha antibodies or with soluble TNFalpha receptors.
Infliximab, a mouse–human chimeric monoclonal anti-TNFalpha antibody, is manufactured by Centocor Inc. Initial administration of 3–5mg/kg of infliximab at day 0, week 2 and week 6 is followed by maintenance treatment with infusions every eight weeks.
Controlled randomised trials demonstrated good efficacy. At week 10, 72% of patients treated with 3mg/kg infliximab and 88% of patients treated with 5mg/kg showed at least 75% improvement in PASI score. The mean response time was four weeks. Treatment with infliximab was generally well tolerated. The most common adverse effects were mild headache, upper respiratory tract infections and infusion reactions. There have been case reports of serious infections, including reactivated tuberculosis; therefore, a tuberculosis skin test should be carried out before administration.(26–29)
Infliximab is approved by the FDA and the EMEA for the indication of Crohn’s disease and rheumatoid arthritis. The EMEA also approved the drug for psoriatic arthritis in October 2004.
Etanercept, a fully human TNF receptor (p75)-Fc fusion protein, consists of the extracellular ligand binding site of human TNFalpha receptor 2 (p75) with the Fc part of human IgG1.(29) It is given as SC injection twice a week (25mg).(30) In a placebo-controlled study, 652 patients were included. Treatment was either 25mg once or twice a week, or 50mg twice a week, compared with placebo, for 12 weeks. After 12 weeks, the PASI fell by over 75% in 14% of patients in the low-dose group, 34% in the medium-dose group and 49% in the high-dose group. This result was improved to 25% in the low-dose, 44% in the medium and 59% in the high-dose group after 24 weeks of treatment.
Enbrel was generally well tolerated. The most commonly observed side-effects were minor injection-site reactions. As the drug may affect a person’s ability to fight infections, physicians should be careful in the case of patients with a history of recurring infections.(30,31)
FDA approval was given for the indication of psoriatic arthritis in January 2002, and for moderate-to-severe psoriasis in patients requiring systemic therapy in April 2004. Since September 2004 it is also approved for psoriasis by the EMEA.
Available evidence shows that biological therapies provide short- and perhaps long-term control of psoriasis, coupled with improved safety, tolerability, convenience and quality of life.(12)
Deutscher Psoriasis Bund (Patient Organisation)